Field of the Invention
This invention is directed to kits of parts comprising in a first container a cyanoacrylate prepolymer composition and in a second container a compatible antimicrobial agent. The kit may additionally contain an applicator means for applying the composition to mammalian skin. These kits provide for compositions useful in situ formation of antimicrobial polymeric cyanoacrylate films on mammalian skin which films are useful as wound dressings, wound bandages, surgical incise drapes, and the like.
References
The following publications, patent applications and patents are cited in this application as superscript numbers:
1 Hawkins, et al., Surgical Adhesive Compositions, U.S. Pat. No. 3,591,676, issued Jul. 6, 1971
2 Halpern, et al., Adhesive for Living Tissue, U.S. Pat. No. 3,667,472, issued Jun. 6, 1972
3 McIntire, et al., Process for the Preparation of Poly(xcex1-Cyanoacrylates), U.S. Pat. No. 3,654,239, issued Apr. 4, 1972
4 Barley, et al., Methods for Treating Non-Suturable Wounds by Use of Cyanoacrylate Adhesives, International Patent Application Publication No. WO 93/25196, published Dec. 23, 1993
5 Barley, et al., Methods for Treating Suturable Wounds by Use of Sutures and Cyanoacrylate Adhesives, U.S. Pat. No. 5,254,132, issued Oct. 19, 1993
6 Barley, et al., Methods for Reducing Skin Irritation From Artificial Devices by Use of Cyanoacrylate Adhesives, U.S. Pat. No. 5,653,789, issued Aug. 5, 1997
7 Rabinowitz, et al., Method of Surgically Bonding Tissue Together, U.S. Pat. No. 3,527,224, issued Sep. 8, 1970
8 Kronenthal, et al., Surgical Adhesives, U.S. Pat. No. 3,995,641, issued Dec. 7, 1976
9 Davydov, et al., Medical Adhesive, U.S. Pat. No. 4,035,334, issued Jul. 12, 1977
10 Waniczek, et al., Stabilized Cyanoacrylate Adhesives Containing Bis-Trialkylsilyl Esters of Sulfuric Acid, U.S. Pat. No. 4,650,826, issued Mar. 17, 1987
11 Askill, et al., xe2x80x9cMethods for Draping Surgical Incision Sitesxe2x80x9d U.S. Pat. No. 5,730,994, issued Mar. 24, 1998
12 Greff, et al., Cyanoacrylate Adhesive Compositions, U.S. Pat. No. 5,480,935, issued Jan. 2, 1996
13 Hagen, et al., xe2x80x9cA Comparison of Two Skin Preps Used in Cardiac Surgical Proceduresxe2x80x9d, AORN Journal, 62(3):393-402 (1995)
14 Ritter, et al., xe2x80x9cRetrospective Evaluation of an Iodophor-Incorporated Antimicrobial Plastic Adhesive Wound Drapexe2x80x9d, Clinical Orthopedics and Related Research, pp. 307-308 (1988)
15 Osuna, et al., xe2x80x9cComparison of an Antimicrobial Adhesive Drape and Povidone-Iodine Preoperative Skin Preparation in Dogsxe2x80x9d, Veterinary Surgery, 21(6):458-462 (1992)
16 O""Sullivan, et al., High Viscosity Cyanoacrylate Adhesive Compositions, and Process for Their Preparation, U.S. Pat. No. 4,038,345, issued Jul. 26, 1977
17 Beller, et al., Process for the Preparation of Iodine-Polyvinylpyrrolidone by Dry Mixing, U.S. Pat. No. 2,706,701, issued Apr. 19, 1955
18 Hosmer, Process of Stabilizing Polyvinylpyrrolidone, U.S. Pat. No. 2,826,532, issued Mar. 11, 1958
19 Siggin, Preparation of Iodine Polyvinylpyrrolidone Adducts, U.S. Pat. No. 2,900,305, issued Aug. 18, 1958
20 Joyner, et al., Plasticized Monomeric Adhesive Compositions and Articles Prepared Therefrom, U.S. Pat. Nos. 2,784,127, issued Mar. 5, 1957
21 Columbus, et al., Adhesive Cyanoacrylate Compositions with Reduced Adhesion to Skin, U.S. Pat. No. 4,444,933, issued Apr. 24, 1984
22 Leung, et al., Biocompatible Monomer and Polymer Compositions, U.S. Pat. No. 5,328,687, issued Jul. 12, 1994
23 Byram, et al., Use of Cyanoacrylate Adhesive Compositions to Inhibit Acute Radiation-Induced Skin Damage, U.S. Pat. No. 5,554,365, issued Sep. 10, 1996.
24 Leplyanin, xe2x80x9cMedical and Surgical Adhesive Composition and Process for Its Preparationxe2x80x9d, International Application Publication No. WO 96/23532 published Aug. 8, 1996
25 Tighe, et al., xe2x80x9cUse of Cyanoacrylate Adhesives For Providing A Protective Barrier Film For The Skinxe2x80x9d, U.S. Pat. No. 5,580,565, issued on Dec. 3, 1996.
26 Cardarelli, et al., xe2x80x9cFilm Forming Antimicrobial Materialxe2x80x9d, U.S. Pat. No. 4,374,126, issued Feb. 15, 1983
27 Barnes, xe2x80x9cBiocidal Complex and Dressing Formed Therefromxe2x80x9d, U.S. Pat. No. 5,051,256, issued Sep. 24, 1991
28 Dell, xe2x80x9cFilm-Forming Composition Containing an Antimicrobial Agent and Methodsxe2x80x9d, U.S. Pat. No. 4,542,012, issued Sep. 17, 1985
29 Brink, et al., xe2x80x9cFilm-Forming Emulsion Containing Iodine and Methods of Usexe2x80x9d, U.S. Pat. No. 5,173,291, issued Dec. 22, 1992
30 Khan, et al., xe2x80x9cPreparation of a Skin Surface for a Surgical Procedurexe2x80x9d, U.S. Pat. No. 5,547,662, issued Aug. 20, 1996
31 Blum, et al., In vitro Determination of the Antimicrobial Properties of Two Cyanoacrylate Preparations, J. Dent. Res., 54(3):500-503 (1975)
32 Greff et al., xe2x80x9cCyanoacrylate Compositions Comprising an Antimicrobial Agentxe2x80x9d, U.S. Pat. No. 5,684,042, issued Nov. 4, 1997
33 Greff et al., xe2x80x9cCyanoacrylate Compositions Comprising an Antimicrobial Agentxe2x80x9d, U.S. patent application No. 08/912,681, filed Aug. 18, 1997
34 Mixon, U.S. Pat. No. 5,069,907
35 Greff, et al., Methods for Sterilizing Cyanoacrylate Compositions, U.S. Pat. No. 6,248,800 which issued on Jun. 19, 2001.
All of the above publications, patent applications and patents are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent application or patent was specifically and individually indicated to be incorporated by reference in its entirety.
State of the Art
Cyanoacrylate esters have been disclosed for a variety of topical uses on mammalian skin including use as a replacement or adjunct for sutures or staples in closing the dermal layer of an incision after surgery.1,2,5 Other disclosed topical uses include use as a hemostat3, use in covering small non-suturable wounds on skin surfaces4, use in inhibiting surface skin irritation arising from friction between the skin surface and artificial devices such as tapes, prosthetic devices, casts, etc.6 and use in inhibiting acute radiation-induced skin damage.23 Still another topical use of cyanoacrylate esters is its use in the in situ formation of a surgical incise drape.11 In each case, when topically applied to mammalian skin, the cyanoacrylate rapidly polymerizes, typically within a minute, to form a coherent polymeric film which strongly adheres to the skin.
Cyanoacrylate esters suggested for such uses include the following structures: 
wherein R is an alkyl or other suitable substituent. Such cyanoacrylate esters are disclosed in, for example, U.S. Pat. Nos. 3,527,224; 3,591,676; 3,667,472; 3,995,641; 4,035,334; and 4,650,826.1,2,7-10 
Cyanoacrylate ester compositions for topical skin application typically are formulated to contain both a plasticizer to enhance flexibility of the resulting polymeric film and a polymerization inhibitor to avoid premature polymerization of the composition. When employed topically on mammalian skin, Greff et al.12 disclose that the cyanoacrylate composition preferably employs from about 50 to about 500 ppm sulfur dioxide as the polymerization inhibitor and from about 18-25 weight percent of a biocompatible plasticizer such as dioctyl phthalate.
Notwithstanding the beneficial properties associated with such cyanoacrylate ester compositions and their suitability for topical applications, these compositions do not possess a sufficient antimicrobial activity including activity against microbial spores31 and, accordingly, cannot assure reductions in microbial populations on mammalian skin surface either under or adjacent to a polymeric cyanoacrylate film formed in situ on the skin.
Many of the uses of cyanoacrylate ester compositions enumerated above would, however, significantly benefit by additional antimicrobial property in the polymer film. For instance, covering small non-suturable wounds on skin surfaces with a polymeric cyanoacrylate film having antimicrobial activity would mitigate against possible wound infection. Likewise, when used as a surgical (incise) drape, such films would reduce microbial populations under and adjacent to the drape including those at the incision site and, accordingly, would reduce the risk of post-operative infection. Such is the basic premise of commercial surgical drapes containing an antimicrobial agent impregnated directly into the drape or an adhesive layer attached thereto where it was hoped that this agent would be released onto the skin surface to inhibit microbial growth.13,14 Osuna, et al.15 report, however, that when the antimicrobial agent is incorporated into the adhesive layer, the adhesive does not release sufficient amounts of the impregnated agent to be, by itself, antimicrobial.
As noted above, cyanoacrylate esters do not possess adequate antimicrobial activity and, accordingly, incorporation of antimicrobial properties into the cyanoacrylate polymeric film necessitates, of course, that an antimicrobially effective amount of an antimicrobial agent be incorporated into the prepolymeric cyanoacrylate composition and that sufficient amounts of this agent be released from the polymeric cyanoacrylate film onto the skin to achieve an antimicrobial effect. The incorporation of such an antimicrobial agent into the cyanoacrylate composition is problematic at best because several disparate criteria must be simultaneously met. First, the antimicrobial agent must be soluble or dispersible in the cyanoacrylate composition at the concentrations necessary to effect antimicrobial properties. Second, the antimicrobial agent employed must not cause premature polymerization of the cyanoacrylate ester composition. Third, the antimicrobial agent employed must not prevent in situ polymerization of the cyanoacrylate composition when applied to the skin. Fourth, the antimicrobial agent must be compatible with the intended use of the poll meric film by not inhibiting formation of a flexible, durable film. Fifth, the impregnated antimicrobial agent must be released from the polymerized film in situ on the patient""s skin in sufficient amounts to be antimicrobial.
Because of these disparate properties, many conventional antimicrobial agents are unsuitable for use in the prepolymeric compositions of this invention and typically the prior art has incorporated an antimicrobial agent into a solution or emulsion of the formed polymer or by direct mixing in the polymer melt (see, for example, Mixon34).
When an antimicrobial agent is incorporated into a solution/emulsion, placement of the solution/emulsion on the patient""s skin followed by subsequent evaporation of the solvent results in a polymer film formed on the skin which film is permeated with the antimicrobial agent.26,28-29 Since the polymer is preformed prior to application to the skin, these solutions/emulsions reduce the effective adherence of the polymer film to the skin and, accordingly, could lead to premature lifting or removal of the film from the skin. Moreover, the use of water and other solvents in the emulsion or solution can lead to slow drying times for the film with the concurrent difficulty in determining when or if the solvent has evaporated sufficiently to provide a polymer film on the patient""s skin.30 Organic solvents, on the other hand, forms noxious and potentially flammable fumes.
Kits containing an antimicrobial cyanoacrylate composition and an applicator means have been described in Greff et al., U.S. patent application No. 08/912,68133. Because the cyanoacrylate composition and the antimicrobial agent are premixed in the kit, such a mixture may have a reduced shelf-life because of the premature polymerization of the cyanoacrylate ester over time (e.g., months). Furthermore, certain antimicrobial agents cannot be formulated in such kits because they cause premature polymerization of the cyanoacrylate ester. Finally, sterilization of the cyanoacrylate/antimicrobial mixture, if desired, may result in premature polymerization of the composition in the container and the various components of the composition may be sterilized. The method of sterilization may be the method set forth in Askill et al.35, U.S. Pat. No. 6,248,800 which issued on Jun. 19, 2001 and which is incorporated by reference.
In view of the clear benefits associated with the incorporation of an antimicrobial agent into the monomeric cyanoacrylate composition prior to application of the cyanoacrylate composition onto mammalian skin, there is a need for a kit which comprises a cyanoacrylate composition in a first container and an antimicrobial agent in a second container such that the composition and agent can be mixed immediately prior to use and the resulting composition applied to mammalian skin.
This invention is directed to kits of parts comprising a polymerizable cyanoacrylate ester composition in a first container and an antimicrobially effective amount of a compatible antimicrobial agent in a second container. When the contents of these containers are mixed, a polymerizable antimicrobial cyanoacrylate composition is provided which permits in situ formation of an antimicrobial polymeric cyanoacrylate film on mammalian skin. The specific antimicrobial agent employed is compatible with the cyanoacrylate composition insofar as the antimicrobial agent neither causes premature polymerization nor prevents polymerization of the monomer. Rather a flexible and durable polymeric film is formed in situ on mammalian skin by the mixture of these two compositions and application of the mixture onto the skin. Moreover, in vitro assays evidence that the antimicrobial agent is released from the polymeric film in antimicrobially effective amounts thereby imparting antimicrobial properties to the polymeric film.
Accordingly, in one of its kit aspects, this invention is directed to kit of parts which comprises:
(a) a first container comprising therein a polymerizable cyanoacrylate ester; and
(b) a second container comprising therein an antimicrobially effective amount of a compatible antimicrobial agent.
Optionally, multiple containers can be used to store separate antimicrobial components if a mixture of more than one antimicrobial agent is employed.
Preferably, the polymerizable cyanoacrylate ester is a polymerizable monomer or reactive oligomer of a cyanoacrylate ester. Such monomers and reactive oligomers are sometimes referred to herein simply as xe2x80x9cprepolymersxe2x80x9d and, in monomeric form, are preferably represented by formula I: 
wherein R is selected from the group consisting of:
alkyl of 1 to 10 carbon atoms,
alkenyl of 2 to 10 carbon atoms,
cycloalkyl groups of from 5 to 8 carbon atoms,
phenyl,
2-ethoxyethyl,
3-methoxybutyl,
and a substituent of the formula: 
xe2x80x83wherein each Rxe2x80x2 is independently selected from the group consisting of: hydrogen and methyl, and
Rxe2x80x3 is selected from the group consisting of:
alkyl of from 1 to 6 carbon atoms,
alkenyl of from 2 to 6 carbon atoms,
alkynyl of from 2 to 6 carbon atoms,
cycloalkyl of from 3 to 8 carbon atoms,
aralkyl selected from the group consisting of benzyl, methylbenzyl and phenylethyl,
phenyl, and
phenyl substituted with 1 to 3 substituents selected from the group consisting of hydroxy, chloro, bromo, nitro, alkyl of 1 to 4 carbon atoms, and alkoxy of from 1 to 4 carbon atoms.
More preferably, in the cyanoacrylate esters of formula I, R is alkyl of from 2 to 10 carbon atoms and still more preferably an alkyl of from 4 to 10 carbon atoms. Even more preferably, R is butyl, pentyl, octyl, decyl or mixtures thereof and most preferably R is n-butyl.
The kit of parts preferably further comprises an effective amount of polymerization inhibitors and a biocompatible plasticizer. Suitable polymerization inhibitors are well known in the art and include 4-methoxyphenol (50 to 1000 ppm based on weight of composition absent any antimicrobial agent) and sulfur dioxide (50 to 1000 ppm based on weight of composition absent any antimicrobial agent). Other preferred polymerization inhibitors include acid inhibitors, e.g., glacial acetic acid and other organic acids, and free radical inhibitors (e.g. hydroquinones, hindered phenols) and the like which can be used alone or in combination with 4-methoxyphenol and/or SO2.
The preferred biocompatible plasticizer is dioctyl phthalate or C2-C4-acyl tri-n-alkyl (C1-C6) citrates. The plasticizer is preferably employed at from about 18 to 25 weight percent based on the total weight of the composition absent the antimicrobial agent.
In one embodiment, the first container of the kit which comprises the cyanoacrylate composition, further comprises the polymerization inhibitor and the biocompatible plasticizer.
In another embodiment, the kit of parts further comprises an applicator means for applying the composition onto mammalian skin which, preferably, is an integral part of one of the containers employed in the kit.